GPC3 (glypican 3)

2002-05-01   Daniel Sinnett 

Division of Hematology-oncology, Research Centre, Sainte-Justine Hospital, 3175 Côte Sainte-Catherine, Montreal, H3T 1C5, Québec, Canada

Identity

HGNC
LOCATION
Xq26.2
LOCUSID
ALIAS
Glypican-3 (GPC3),MXR7,OCI-5,GTR2-2
FUSION GENES

DNA/RNA

Description

The gene spans more than 500 kb of DNA consisting of 8 exons.

Transcription

2.2kb mRNA; 1740 bp open reading frame.

Proteins

Description

580 amino acids; 65 kDa protein. GPC3 is a heparan sulfate proteoglycan (HSPG) that is attached to the cell surface via a glycosyl-phosphatidylinositol (GPI) anchor.

Expression

GPC3 is highly expressed in embryonal tissues such as the developing intestine and the mesoderm-derived tissues, and its expression is downregulated in most adult tissue.

Localisation

Attached to the membrane by a GPI anchor.

Function

The biochemical function of GPC3 has yet to be established. HSPG may be involved in the suppression/modulation of growth in the predominantly mesodermal tissues and organs; may play a role in the modulation of IGF-II interactions with its receptor and thereby modulate its function; can have a potential role as a regulator of growth and tumor predisposition. Therefore it is likely that GPC3 is able not only to bind more than one growth factor, but also to functionally affect the signalling of different growth factors. A role for GPC3 in the regulation of insulin-like growth (IGF) factors has been proposed. IGF-II is a growth factor that can act as a survival factor in the early stages of tumourigenesis. The co-expression of GPC3 and IGF-II has been observed in embryonal tumors as well as in mouse foetal tissues; GPC3 expression is able to induce apoptosis in a cell-specific manner, but this effect could be reversed by the addition of IGF peptides; IGFs could be needed to prevent GPC3-induced apoptosis in any cell, allowing cellular responses to other factors to take place and be mediated, enhanced or inhibited by GPC3; GPC3 mutations lead to SGBS (see below), a syndrome that shares significant similarities with the Beckwith-Wiedemann syndrome that is an overgrowth syndrome that is thought to be associated with increased expression of IGF2.

Homology

Belongs to the glypican family; six members, glypican-1 to 6, have been identified in mammalians; the protein core of glypicans are 20-50% identical; The glypican family is represented by at least two known members in Drosophila, dally and dally-like.

Mutations

Germinal

Most known mutations are deletions involving different exons of GPC3; missense, nonsense as well as splicing site mutations.

Somatic

The expression of GPC3 is altered in cancer cells. GPC3 is upregulated in hepatocellular carcinoma, in Wilms tumor and in metastatics colorectal malignancie. With regard to tumours with neuronal phenotype, GPC3 was detected at variable levels in a neurofibrosarcoma and in most neuroblastomas, but was absent from medulloblastomas. These findings suggest that GPC3 expression is differentially regulated in the various cell lineages giving rise to pediatric tumours of the peripheral and central nervous systems. On the other hand, GPC3 is frequently silenced in mesotheliomas, in ovarian cancer cell lines and in breast cancer, often due to hypermethylation of the GPC3 promoter.

Implicated in

Entity name
Simpson-Golabi-Behmel Syndrome (SGBS)
Disease
X-linked disease characterized by a wide variety of clinical manifestations, including pre- and post-natal overgrowth, tissue dysplasia, in particular of the kidneys, and cardiac anomalies; associated with a greater risk of developing embryonal cancers; caused by loss-of-function mutation in the GPC3 gene ; the abnormalities found in SGBS patients suggest that GPC3 might be involved in the regulation of growth and/or apoptosis during development.

Bibliography

Pubmed IDLast YearTitleAuthors
112865012001Simpson Golabi Behmel syndrome: progress toward understanding the molecular basis for overgrowth, malformation, and cancer predisposition.DeBaun MR et al
113200542001Glypicans in growth control and cancer.Filmus J et al
31855471988Isolation of a cDNA corresponding to a developmentally regulated transcript in rat intestine.Filmus J et al
93715211997Cloning and expression of a developmentally regulated transcript MXR7 in hepatocellular carcinoma: biological significance and temporospatial distribution.Hsu HC et al
16052221992Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21.Hughes-Benzie RM et al
93744071997dally, a Drosophila glypican, controls cellular responses to the TGF-beta-related morphogen, Dpp.Jackson SM et al
110910942000Dally-like protein, a new Drosophila glypican with expression overlapping with wingless.Khare N et al
94761511998Expression of the novel mitoxantrone resistance associated gene MXR7 in colorectal malignancies.Lage H et al
96300661998Overgrowth syndromes and genomic imprinting: from mouse to man.Li M et al
100290671999Frequent silencing of the GPC3 gene in ovarian cancer cell lines.Lin H et al
104213721999Dally cooperates with Drosophila Frizzled 2 to transduce Wingless signalling.Lin X et al
93594321997Glypican-3 is a binding protein on the HepG2 cell surface for tissue factor pathway inhibitor.Mast AE et al
106566892000Expression of GPC3, an X-linked recessive overgrowth gene, is silenced in malignant mesothelioma.Murthy SS et al
85822811995The division abnormally delayed (dally) gene: a putative integral membrane proteoglycan required for cell division patterning during postembryonic development of the nervous system in Drosophila.Nakato H et al
97819081998Clinical and molecular aspects of the Simpson-Golabi-Behmel syndrome.Neri G et al
98539641998Gpc3 expression correlates with the phenotype of the Simpson-Golabi-Behmel syndrome.Pellegrini M et al
85897131996Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome.Pilia G et al
110082032000Expression of glypican 3 (GPC3) in embryonal tumors.Saikali Z et al
90654091997OCI-5/rat glypican-3 binds to fibroblast growth factor-2 but not to insulin-like growth factor-2.Song HH et al
104213711999The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila.Tsuda M et al
107166252000Heparan sulfate proteoglycans on the cell surface: versatile coordinators of cellular functions.Tumova S et al
108147142000Mutational analysis of the GPC3/GPC4 glypican gene cluster on Xq26 in patients with Simpson-Golabi-Behmel syndrome: identification of loss-of-function mutations in the GPC3 gene.Veugelers M et al
117048702001Glypican-3 expression is silenced in human breast cancer.Xiang YY et al

Other Information

Locus ID:

NCBI: 2719
MIM: 300037
HGNC: 4451
Ensembl: ENSG00000147257

Variants:

dbSNP: 2719
ClinVar: 2719
TCGA: ENSG00000147257
COSMIC: GPC3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000147257ENST00000370818P51654
ENSG00000147257ENST00000370818I6QTG3
ENSG00000147257ENST00000394299P51654
ENSG00000147257ENST00000406757H0Y3U6
ENSG00000147257ENST00000631057P51654

Expression (GTEx)

0
50
100
150
200
250

Pathways

PathwaySourceExternal ID
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
DiseaseREACTOMER-HSA-1643685
Diseases of glycosylationREACTOMER-HSA-3781865
Diseases associated with glycosaminoglycan metabolismREACTOMER-HSA-3560782
Defective B4GALT7 causes EDS, progeroid typeREACTOMER-HSA-3560783
Defective B3GAT3 causes JDSSDHDREACTOMER-HSA-3560801
Defective EXT1 causes exostoses 1, TRPS2 and CHDSREACTOMER-HSA-3656253
Defective EXT2 causes exostoses 2REACTOMER-HSA-3656237
Signal TransductionREACTOMER-HSA-162582
Visual phototransductionREACTOMER-HSA-2187338
Retinoid metabolism and transportREACTOMER-HSA-975634
MetabolismREACTOMER-HSA-1430728
Metabolism of carbohydratesREACTOMER-HSA-71387
Glycosaminoglycan metabolismREACTOMER-HSA-1630316
Heparan sulfate/heparin (HS-GAG) metabolismREACTOMER-HSA-1638091
A tetrasaccharide linker sequence is required for GAG synthesisREACTOMER-HSA-1971475
HS-GAG biosynthesisREACTOMER-HSA-2022928
HS-GAG degradationREACTOMER-HSA-2024096
Chondroitin sulfate/dermatan sulfate metabolismREACTOMER-HSA-1793185
Metabolism of vitamins and cofactorsREACTOMER-HSA-196854
Defective B3GALT6 causes EDSP2 and SEMDJL1REACTOMER-HSA-4420332
Metabolism of fat-soluble vitaminsREACTOMER-HSA-6806667

References

Pubmed IDYearTitleCitations
170879382006A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis.101
194967872009Glypican-3 expression is correlated with poor prognosis in hepatocellular carcinoma.85
166755602006Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma.62
124786602003Glypican-3, overexpressed in hepatocellular carcinoma, modulates FGF2 and BMP-7 signaling.58
192310032009The application of markers (HSP70 GPC3 and GS) in liver biopsies is useful for detection of hepatocellular carcinoma.52
207259052010The oncogenic effect of sulfatase 2 in human hepatocellular carcinoma is mediated in part by glypican 3-dependent Wnt activation.45
244929432014Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy.45
244964492014Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling.44
154754512004Identification of glypican-3 as a novel tumor marker for melanoma.43
275730792016Long noncoding RNA glypican 3 (GPC3) antisense transcript 1 promotes hepatocellular carcinoma progression via epigenetically activating GPC3.41

Citation

Daniel Sinnett

GPC3 (glypican 3)

Atlas Genet Cytogenet Oncol Haematol. 2002-05-01

Online version: http://atlasgeneticsoncology.org/gene/156/gpc3